CN111793103B - Extraction process of apramycin sulfate - Google Patents
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Abstract
The invention discloses an extraction process of apramycin sulfate, which is characterized in that apramycin fermentation liquor is subjected to membrane dialysis, resin adsorption, resin desorption and salifying drying to obtain a finished product of apramycin sulfate, and the extraction process has feasibility and simple operation steps when applied to production. After being enriched by using a ceramic membrane technology, the thalli are incinerated. The process is green and environment-friendly, can reduce the total ammonia nitrogen value in the wastewater, and can obtain higher product titer and purity.
Description
Technical Field
The invention relates to an extraction process of veterinary antibiotics, in particular to an extraction process of apramycin sulfate, and belongs to the field of pharmaceutical chemicals.
Background
The apramycin synthesized by streptomyces atrophaeus is a novel broad-spectrum veterinary antibiotic, is developed into a product by American etiquette companies in the 80 s, is a two-class novel veterinary drug approved in the 2000 s of China, and has high antibacterial activity on gram-negative bacteria and staphylococcus. Because the molecule has unique octanediose structure different from other aminoglycoside antibiotics, the compound has the functions of inhibiting and killing drug-resistant bacteria of various aminoglycoside antibiotics, is not easy to produce cross drug resistance in use, and has the characteristics of low toxicity, low residual quantity and safety. Has strong antibacterial activity to gram-negative bacteria infected by livestock and poultry, and is especially suitable for escherichia coli and salmonella with strong drug resistance. As a drug feed additive, the compound feed additive can also obviously promote weight gain and improve feed conversion rate, and is widely applied to the prevention and treatment of diseases such as acute and chronic diarrhea, enteritis and the like of livestock and poultry caused by escherichia coli, salmonella and the like.
The apramycin is synthesized by fermentation of Streptomyces atrophaeus, and Chinese patent application with publication number CN102477052B discloses a method for extracting apramycin from Streptomyces atrophaeus (Streptomyces tenebrarius) fermentation liquor for producing carbamoyltobramycin, and the extraction process comprises the following steps: adjusting the pH value of an apramycin and carbamyl tobramycin fermentation solution to 5-6, adsorbing by using strong acid styrene cation exchange resin, eluting by using ammonia water to obtain a mixed crude solution of the apramycin and the carbamyl tobramycin, hydrolyzing the mixed crude solution to obtain a tobramycin crude solution containing apramycin, adjusting the pH value of the tobramycin crude solution containing apramycin to 8-9, adsorbing by using macroporous acrylic acid series weak acid cation exchange resin, eluting by using ammonia water, and further purifying the obtained apramycin solution, wherein the apramycin solution is purified by using a series column of macroporous acrylic acid series weak acid cation exchange resin and strong base styrene series anion exchange resin, and crystallizing to obtain the apramycin.
A method for preparing apramycin (Urzongzi et al, "study of Niramycin single component-apramycin high-producing strain", China J antibiotics, 1997, Vol.22, No. 5, p.334, 339, 350) is reported by Urzongzi et al, wherein after fermentation is completed, fermentation liquor is treated by acid and alkali to remove acid and alkali proteins, and then 110 (NH)4 +Type) ion exchange resin is subjected to static adsorption, then the resin is washed by brine-free water, ammonia water is used for elution, eluent is collected, and the white pure product is obtained after the eluent is concentrated, decolored and vacuum freeze-dried.
The process method is mature, but the method uses a large amount of ammonia water for elution, cannot be applied to large-scale production under the severe situation of current environmental protection, and does not relate to a method for treating residual thallus dregs after fermentation liquor is adsorbed by resin.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the extraction process of apramycin sulfate, which is green and environment-friendly, the fermentation liquor is pretreated by using the ceramic membrane, the thallus dregs are effectively removed, the resin is conveniently recycled, and meanwhile, the resin adopts dynamic adsorption, so that the automation and the sealing of the operation are realized; the total ammonia nitrogen value in the wastewater can be reduced by adopting the alternative solvent for elution, and higher product titer and purity can be obtained.
An extraction process of apramycin sulfate comprises the following steps:
(1) adding acid into fermentation liquor of apramycin for pretreatment;
(2) circularly dialyzing the pretreated fermentation liquor by adopting a ceramic membrane to respectively obtain dialysate containing apramycin and concentrated thallus dregs;
(3) adding alkali into the dialysate, and adsorbing with weak acid cation resin column;
(4) connecting the cation resin column after adsorption in the step (3) with an anion resin column in series, then adding acid to the weakly acidic cation resin column for analysis, and collecting an analysis solution from an outlet of the anion resin column;
(5) and (3) permeating the analytic solution through a nanofiltration membrane to obtain a high-concentration apramycin solution, and then adding sulfuric acid to salify at controlled temperature and drying to obtain the apramycin sulfate.
The apramycin sulfate finished product is obtained by performing membrane dialysis, resin adsorption, resin desorption and salifying drying on the apramycin solution, the whole process is green, environment-friendly and simple, all indexes of the obtained apramycin sulfate finished product meet the requirements of Chinese veterinary drug classics, and the total titer yield is more than 85%.
In the invention, the preparation of the fermentation liquor is the prior art, the fermentation liquor prepared by the patent methods of CN 104232709A, CN 109593807A and the like can be extracted by adopting the method of the invention, and the use of the patent process method is not influenced as long as apramycin is from fermentation.
In the step (1), the acid is at least one selected from hydrochloric acid, sulfuric acid, oxalic acid, acetic acid, citric acid and formic acid, preferably oxalic acid, and the pH value after pretreatment is 1.5-6.5, preferably 1.5-2.5.
In the step (2), the aperture of the ceramic membrane is selected to be 2 nm-200 nm, preferably 5 nm-50 nm, and the permeation pressure during dialysis is 0.05 MPa-0.20 MPa, preferably 0.05 MPa-0.10 MPa. The thalli can be enriched through the treatment in the steps (1) and (2) and then are incinerated, so that the improvement of the product purity is facilitated, and the thalli are removed in advance, so that the recovery and the reuse of the resin are facilitated.
In the step (3), the alkali is at least one of sodium hydroxide and potassium hydroxide, preferably sodium hydroxide; the pH value after the addition of the alkali is 5.0-14, preferably 6.0-7.0.
In the step (3), the kind of the cationic resin is at least one of SQD-80, SQD-85 and SQD-112, and more preferably SQD-112, which has a large influence on the separation effect.
In the step (3), the column feeding speed is 0.5 BV/H-3 BV/H, preferably 2 BV/H-3 BV/H.
In step (4), the anion resin is selected from strongly basic styrene-based anion exchange resins, such as 201 × 4(711), D202, preferably 711.
In the step (4), the acid is at least one of hydrochloric acid, sulfuric acid, formic acid, acetic acid, citric acid and oxalic acid.
In the step (4), the concentration of the acid is 0.05-4 mol/L, preferably 0.1-2 mol/L.
In the step (4), the analytic flow rate of the acid on the column is 0.1-3 BV/H, preferably 0.5 BV/H-2.0 BV/H.
In the step (5), the specification of the nanofiltration membrane is 150-300 Da, preferably 150-200 Da.
In the step (5), the concentration of the sulfuric acid is 1-6 mol/L, and preferably 2-4 mol/L.
In the step (5), the temperature of the sulfuric acid salt forming is 4-40 ℃, and preferably 4-25 ℃.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention adopts the ceramic membrane to dialyze the pretreated fermentation liquor, can efficiently collect the bacterial residues, and can achieve the sealing and automation of the operation.
(2) The resin adsorption adopts dynamic adsorption, and can provide a foundation for the automatic ion exchange operation of the product.
(3) In the resin step, an acid pickling and stripping process is adopted, so that the total ammonia nitrogen value in the wastewater is obviously reduced.
(4) The acid washing and removing process is carried out, the yield is obviously reduced by using the commonly used hydrogen type cation resin, and the invention screens the proper resin and combines the acid washing and removing process, thereby improving the product yield, obviously improving the unit titer of the product, reducing the total impurity purity, the maximum single impurity purity and the like.
Detailed Description
The present invention is further illustrated by the following examples, which are described in more detail and detail, but not to be construed as limiting the scope of the invention, but rather as embodying the invention in equivalent substitution or equivalent transformation.
The fermentation liquid of apramycin with different titer obtained by the existing methods such as Niramycin single-component apramycin high-producing strain research (1997, Uroney et al), "Anpramycin producing strain research (2002, Tianwei et al), CN 104232709A, CN 109593807A and the like can be used for the preparation of the application, the fermentation liquid of apramycin with different titer in the following specific examples can be respectively obtained by the method, and the titer of the fermentation liquid in the specific examples is only used for illustrating the effect of the invention and is not to be construed as limiting the invention.
Example 1
Pretreatment: to 5L of fermentation broth (the titer of the fermentation broth is 8150u/mL) obtained by fermentation and containing apramycin, solid oxalic acid is added to adjust the pH of the fermentation broth to 1.6.
Membrane dialysis: pumping the acid-adjusted apramycin fermentation liquor into a ceramic membrane with the membrane aperture of 50nm for circulating dialysis, controlling the pressure at the outlet of the dialysate to be 0.1MPa +/-0.02, collecting the dialysate containing apramycin, wherein the residue in the ceramic membrane is concentrated thallus residue with the solid content of more than 40%, and carrying out incineration treatment after collection.
Resin step: adding liquid alkali into the dialysate to adjust the pH to 6.5, loading onto a column, wherein the filling material in the column is SQD-112 type cationic resin, after loading the dialysate onto the column at the flow rate of 2BV/H, washing with a proper volume of purified water until the effluent is colorless by visual inspection, after washing, adding 0.2M hydrochloric acid aqueous solution until the SQD-112 cationic resin begins to analyze at the analysis flow rate of 1BV/H, decoloring the analysis solution with 711 type anionic resin, and collecting the decolored solution.
Salifying and drying: and (3) permeating water into the decolorized solution through a nanofiltration membrane with the membrane aperture of 200Da, collecting the concentrated solution to obtain an apramycin concentrated solution with the titer of 10 ten thousand ug/mL, slowly adding 4mol/L sulfuric acid solution to carry out salt conversion at the temperature of 10 ℃, and carrying out spray drying on the converted solution to obtain 69.69g of an apramycin sulfate finished product with the yield of 88.26%.
The total ammonia nitrogen value in the obtained wastewater is shown in table 1, the obtained finished product is detected according to the standard of the first edition of Chinese veterinary pharmacopoeia 2010, and the product titer, the total impurity purity, the maximum single impurity purity and the like are shown in table 2.
Example 2
Pretreatment: fermenting to obtain 5L fermentation liquid (the titer of the fermentation liquid is 6500u/mL) containing apramycin, and adding solid oxalic acid to adjust the pH of the fermentation liquid to 3.4.
Membrane dialysis: pumping the acid-adjusted apramycin fermentation liquor into a ceramic membrane with the membrane aperture of 30nm for circulating dialysis, controlling the pressure at the outlet of the dialysate to be 0.15MPa +/-0.02, collecting the dialysate containing apramycin, wherein the residue in the ceramic membrane is concentrated thallus residue with the solid content of more than 40%, and carrying out incineration treatment after collection.
Resin step: adding liquid alkali into the dialysate to adjust the pH to 7.0, loading the dialysate into a column at a flow rate of 2BV/H, wherein the column is filled with SQD-85 type cationic resin, after loading the dialysate into the column, washing the column with a proper volume of purified water until the effluent is colorless by visual observation, after washing, adding 0.1mol/L sulfuric acid aqueous solution until the SQD-85 type cationic resin begins to be analyzed, wherein the analysis flow rate is 2BV/H, decolorizing the analysis solution through 711 anionic resin, and collecting decolorized solution.
Step E
Salifying and drying: and (3) permeating water into the decolored solution through a nanofiltration membrane with the membrane aperture of 200Da, collecting the concentrated solution to obtain an apramycin concentrated solution with the titer of 10 ten thousand ug/mL, controlling the temperature at 20 ℃, slowly adding 2mol/L sulfuric acid solution for salt conversion, and performing spray drying on the converted solution to obtain 56.46g of apramycin sulfate finished product, wherein the finished product is white powder in appearance, and the yield is 86.89%.
Example 3
Pretreatment: fermenting to obtain 5L fermentation liquid (the titer of the fermentation liquid is 8150u/mL) containing apramycin, and adding solid oxalic acid to adjust the pH of the fermentation liquid to 2.4.
Membrane dialysis: pumping the acid-adjusted apramycin fermentation liquor into a ceramic membrane with the membrane aperture of 50nm for circulating dialysis, controlling the pressure at the outlet of the dialysate to be 0.1MPa +/-0.02, collecting the dialysate containing apramycin, wherein the residue in the ceramic membrane is concentrated thallus residue with the solid content of more than 40%, and carrying out incineration treatment after collection.
Resin step: adjusting the pH of the dialysate to 7.0 by using liquid alkali, loading the dialysate into a column at a flow rate of 2BV/H, wherein the column is filled with SQD-80 type cationic resin, washing the column with purified water 2 times the volume of the resin after loading the dialysate, preparing 1.25mol/L acetic acid aqueous solution for analysis after washing, performing decoloration on the analysis solution by using D202 type anionic resin at an analysis flow rate of 1.5BV/H, and collecting decolored solution.
Salifying and drying: and (3) permeating water into the decolored solution through a nanofiltration membrane with the membrane aperture of 200Da, collecting the concentrated solution to obtain an apramycin concentrated solution with the titer of 10 ten thousand ug/mL, controlling the temperature at 20 ℃, slowly adding 4mol/L sulfuric acid solution for salt conversion, and performing spray drying on the converted solution to obtain 39.05g of an apramycin sulfate finished product, wherein the appearance of the finished product is white powder, and the yield is 56%.
Example 4
Pretreatment: fermenting to obtain 5L fermentation liquid (the titer of the fermentation liquid is 4500u/mL) containing apramycin, and adding solid oxalic acid to adjust the pH of the fermentation liquid to 2.0.
Membrane dialysis: pumping the acid-adjusted apramycin fermentation liquor into a ceramic membrane with the membrane aperture of 30nm for circulating dialysis, controlling the pressure at the outlet of the dialysate to be 0.1MPa +/-0.02, collecting the dialysate containing apramycin, wherein the residue in the ceramic membrane is concentrated thallus residue with the solid content of more than 40%, and carrying out incineration treatment after collection.
Resin step: adding liquid alkali into the dialysate to adjust the pH to 6.75, loading the dialysate into a column at a flow rate of 2.0BV/H, filling an SQD-112 type cationic resin into the column, washing the dialysate with purified water 2 times the volume of the resin after loading the column, respectively preparing 0.5mol/L citric acid aqueous solution and 1mol/L sulfuric acid aqueous solution into the SQD-112 cationic resin for gradient analysis at an analysis flow rate of 1BV/H, decoloring the analysis solution with D202 type anionic resin, and collecting decolored solution.
Salifying and drying: and (3) permeating water into the decolored solution through a nanofiltration membrane with the membrane aperture of 200Da, collecting the concentrated solution to obtain an apramycin concentrated solution with the titer of 10 wu/mL, controlling the temperature at 20 ℃, slowly adding 4mol/L sulfuric acid solution for salt conversion, and performing spray drying on the converted solution to obtain 32.31g of apramycin sulfate finished product, wherein the finished product is white powder in appearance, and the yield is 83.65%.
Example 5
Pretreatment: fermenting to obtain 5L fermentation liquid (the titer of the fermentation liquid is 3200u/mL) containing apramycin, and adding solid oxalic acid to adjust the pH of the fermentation liquid to 5.4.
Membrane dialysis: pumping the acid-adjusted apramycin fermentation liquor into a ceramic membrane with the membrane aperture of 50nm for circulating dialysis, controlling the pressure at the outlet of the dialysate to be 0.1MPa +/-0.02, collecting the dialysate containing apramycin, wherein the residue in the ceramic membrane is concentrated thallus residue with the solid content of more than 40%, and carrying out incineration treatment after collection.
Resin step: adding liquid alkali into the dialysate, adjusting pH to 7.5, loading onto column, using SQD-80 type cationic resin as filling material, washing with purified water 2 times of resin volume after dialysate loading onto column, adding 2mol/L hydrochloric acid aqueous solution until SQD-80 type cationic resin is resolved at resolving speed of 0.5BV/H, decoloring the resolved solution with 711 type anionic resin, and collecting decolored solution.
Salifying and drying: and (3) permeating water into the decolored solution through a nanofiltration membrane with the membrane aperture of 200Da, collecting the concentrated solution to obtain an apramycin concentrated solution with the titer of 10 ten thousand ug/mL, controlling the temperature at 45 ℃, slowly adding 4mol/L sulfuric acid solution for salt conversion, and performing spray drying on the converted solution to obtain an apramycin sulfate finished product of 20.92g, wherein the appearance of the finished product is off-white powder, and the yield is 76.4%.
Example 6
Pretreatment: fermenting to obtain 5L fermentation liquor (the titer of the fermentation liquor is 8500u/mL) containing apramycin, and adding solid oxalic acid to adjust the pH of the fermentation liquor to 4.5.
Membrane dialysis: pumping the acid-adjusted apramycin fermentation liquor into a ceramic membrane with the membrane aperture of 50nm for circulating dialysis, controlling the pressure at the outlet of the dialysate to be 0.1MPa +/-0.02, collecting the dialysate containing apramycin, wherein the residue in the ceramic membrane is concentrated thallus residue with the solid content of more than 40%, and carrying out incineration treatment after collection.
Resin step: adding liquid alkali into the dialysate to adjust pH to 10.0, loading onto column, wherein the column is filled with SQD-112 type cationic resin, adding 1M hydrochloric acid aqueous solution after the dialysate is loaded onto the column at a flow rate of 3BV/H until the SQD-112 cationic resin begins to analyze at an analysis flow rate of 1BV/H, decolorizing the solution with 711 type anionic resin, and collecting decolorized solution.
Salifying and drying: and (3) permeating water into the decolorized solution through a nanofiltration membrane with the membrane aperture of 200Da, collecting the concentrated solution to obtain an apramycin concentrated solution with the titer of 10 ten thousand ug/mL, slowly adding 4mol/L sulfuric acid solution to convert the salt at 10 ℃, and performing spray drying on the converted solution to obtain 54.25g of apramycin sulfate finished product with the yield of 74.6%.
Comparative example 1
Pretreatment: fermenting to obtain 5L fermentation liquid (the titer of the fermentation liquid is 8150u/mL) containing apramycin, and adding solid oxalic acid to adjust the pH of the fermentation liquid to 6.5.
Resin adsorption: adding ammonia water into the acid-adjusted apramycin fermentation liquor, adjusting the pH value to be neutral, and adding 110 (NH)4 +Type) cationic resin, performing static adsorption, repeatedly rinsing with purified water after adsorption, obtaining resin with residual bacteria-free bodies after rinsing, removing bacteria from rinsing wastewater through plate-and-frame filter pressing, and discharging the wastewater after the wastewater is qualified.
Resin analysis: and filling the rinsed resin into a resin column, resolving by using 2mol/L ammonia water, and directly feeding the resolving solution into D202 type strongly basic anion resin for decolorization.
Salifying and drying: and (3) permeating water into the decolored solution through a nanofiltration membrane with the membrane aperture of 200Da, collecting the concentrated solution to obtain an apramycin concentrated solution with the titer of 10 ten thousand ug/mL, slowly adding 4mol/L sulfuric acid solution to carry out salt conversion at the temperature of 20 ℃, and carrying out spray drying on the converted solution to obtain 58.47g of an apramycin sulfate finished product, wherein the appearance of the finished product is yellow, and the yield is 78.25%.
The total ammonia nitrogen value of the obtained wastewater is shown in table 1, and the titer, total impurity purity, maximum single impurity purity and the like of the obtained product are shown in table 2.
TABLE 1 Total Ammonia Nitrogen values for example 1 and comparative example 1
| Serial number | Process for the preparation of a coating | Total ammonia nitrogen value g/kg product |
| 1 | Example 1 | 62 |
| 2 | Comparative example 1 | 600 |
The results in Table 1 show that the total ammonia nitrogen value in the wastewater in example 1 is obviously reduced compared with the ammonia water elution process when 1kg of product is produced.
Table 2 product potency, total impurity purity, maximum single impurity purity of example 1 and comparative example 1
The results in table 2 show that the ammonia water elution process of example 1 has significant advantages in yield, product titer, total impurity purity, maximum single impurity purity, and the like, compared with the ammonia water elution process of comparative example 1.
Claims (6)
1. An extraction process of apramycin sulfate is characterized by comprising the following steps:
(1) adding acid into fermentation liquor of apramycin for pretreatment;
(2) dialyzing the pretreated fermentation liquor by adopting a ceramic membrane to respectively obtain dialysate containing apramycin and concentrated thallus dregs;
(3) adding alkali into the dialysate, and then performing dynamic adsorption by using a cation resin column;
in the step (3), the resin in the cationic resin column is at least one of SQD-80 resin, SQD-85 resin or SQD-112 resin;
(4) connecting the cation resin column and the anion resin column after adsorption in the step (3) in series, then adding acid to the cation resin column for analysis, and collecting an analysis solution from an outlet of the anion resin column;
in the step (4), the acid is selected from at least one of hydrochloric acid, sulfuric acid, formic acid, acetic acid, citric acid and oxalic acid, and the flow rate of the acid on the column is 0.5-3 BV/H;
(5) and (3) permeating the analytic solution through a nanofiltration membrane to obtain a high-concentration apramycin solution, and then adding sulfuric acid to salify and dry to obtain the apramycin sulfate.
2. The extraction process of apramycin sulfate according to claim 1, wherein in step (1), the acid is at least one selected from hydrochloric acid, sulfuric acid, oxalic acid, acetic acid, citric acid, and formic acid, and the pH value after pretreatment is 1.5-6.5.
3. The extraction process of apramycin sulfate according to claim 1, wherein in step (2), the ceramic membrane has a pore size of 2nm to 200nm, and the permeation pressure during dialysis is 0.05MPa to 0.20 MPa.
4. The extraction process of apramycin sulfate according to claim 1, wherein in step (3), the alkali is at least one of sodium hydroxide and potassium hydroxide, and the pH value after the alkali is added is 5.0-14.
5. The extraction process of apramycin sulfate according to claim 1, characterized in that in step (4), the resin in the anion resin column is a strongly basic anion exchange resin.
6. The extraction process of apramycin sulfate according to claim 1, wherein in step (5), the nanofiltration membrane is 150-300 Da in size.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPS55102397A (en) * | 1979-01-30 | 1980-08-05 | Kowa Co | Preparation of apramycin |
| CN101648982B (en) * | 2009-09-22 | 2011-09-28 | 南阳普康药业有限公司 | Method for recycling gentamicin from waste active carbon generated by discoloring gentamycin sulfate |
| CN102477052B (en) * | 2010-11-26 | 2014-01-15 | 北大方正集团有限公司 | Method for extracting apramycin |
| CN104232709A (en) * | 2014-09-28 | 2014-12-24 | 河北圣雪大成制药有限责任公司 | Method for preparing apramycin through fermentation |
| CN104610395B (en) * | 2015-01-19 | 2018-07-13 | 河北圣雪大成制药有限责任公司 | A method of extracting neomycinsulphate from neomycinsulphate zymotic fluid |
| CN106083952A (en) * | 2016-08-22 | 2016-11-09 | 河北圣雪大成制药有限责任公司 | A kind of method extracting gentamycin sulfate from gentamicin fermentation broth |
| CN106928288B (en) * | 2017-03-21 | 2019-06-28 | 华北制药华胜有限公司 | A kind of preparation method of dihydrostreptomycin sulfate |
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